NOVEL PROCESSES FOR THE MANUFACTURE OF PROPANE-1-SULFONIC ACID (3-[5-(4-CHLORO-PHENYL)-1H-PYRROLO[2,3-b]PYRIDINE-3-CARBONYL]-2,4-DIFLUORO-PHENYL)-AMIDE

ABSTRACT

According to the present invention there are provided novel processes for the manufacture of the compound of formula 1 
     
       
         
         
             
             
         
       
     
     as well as intermediates and novel synthesis routes for key intermediates used in those processes.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.10170266.0, filed Jul. 21, 2010, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is related to alternative synthesis routes toobtain the compound Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(formula 1).

The synthesis of the compound of formula 1 has been described before inWO 2007002433 and WO 2007002325.

The present invention discloses alternative reactions to obtaincompound 1. The reactions and processes disclosed herein use fewreaction steps, and lead to good overall yield of compound 1, inter aliadue to few separation steps and work-up procedures. Moreover, theprocesses disclosed herein can be carried out with relatively smallamounts of starting material and may therefore be safer for use in largescale production, interesting from a cost perspective andenvironmentally friendly. In addition, the present invention providesnovel synthesis methods to obtain key intermediates used in themanufacture of the compound of formula 1. One group of said keyintermediates involves 5-substituted-7-azaindoles. Another group of keyintermediates involves pinacol vinylboronates.

SUMMARY OF THE INVENTION

The present invention relates in part to a process for the manufactureof the compound of formula 1,

comprising at least one Suzuki-Miyaura reaction followed by aFriedel-Crafts acylation.

The present invention also relates to a process for the manufacture of acompound of formula A,

The present invention further relates to a process for the manufactureof the compound of formula D

whereinR¹, R², R³ and R⁴ are all methyl, or together with the carbon atoms towhich they are attached form a phenyl ring; andR⁵ is —(C1-C6)alkyl or benzyl.

In addition, the present invention relates to a compound of formula E

wherein

-   R is phenyl, which is unsubstituted or once or several times    substituted by halogen, or —Br;-   R⁵ is —(C1-C6)alkyl or benzyl; and-   Y¹ and Y² are each independently selected from the group consisting    of benzyl, trifluoroacetyl, acetyl, and hydrogen.

The present invention further relates to a compound of formula F

wherein

-   R is phenyl, which is unsubstituted or once or several times    substituted by halogen, or —Br; and-   Y¹ and Y² are each independently selected from the group consisting    of benzyl, trifluoroacetyl, acetyl, and hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment the present invention provides a process for themanufacture of the compound of formula 1,

comprising at least one Suzuki-Miyaura reaction followed by aFriedel-Crafts acylation.

In another embodiment the present invention provides a process for themanufacture of the compound of formula 1, comprising two Suzuki-Miyaurareactions followed by a Friedel-Crafts acylation.

In another embodiment the present invention provides a process for themanufacture of the compound of formula 1, comprising one Suzuki-Miyaurareaction followed by a Sonogashira reaction, further followed by aFriedel-Crafts acylation.

In a preferred embodiment according to the present invention, the firstSuzuki-Miyaura reaction in each of the processes as described above isfollowed by a halogenation reaction, in particular a reaction step forintroducing a halogen atom, preferably iodo or bromo, into thecorresponding intermediate.

More particularly, there is provided a process for the manufacture ofthe compound of formula 1, wherein

-   -   a) the compound of formula 2

is reacted in the presence of a palladium catalyst, a base and thecompound of formula 3 (1^(st) Suzuki-Miyaura reaction)

to give the compound of formula 4

b) said compound of formula 4 is further reacted in the presence of ahalogenation reagent to give a compound of formula 5

wherein X is I (5a) or Br (5b); andsaid compound of formula 5 is further reacted in the presence of either

c-1) a compound of formula (D) (2^(nd) Miyaura reaction); or

c-2) a compound of formula 7 (Sonogashira reaction)

to give the compound of formula 8

and

d) said compound of formula 8 is subsequently reacted in the presence ofthe compound of formula 9 and under the conditions of a Friedel-CraftsAcylation

to give the compound of formula 1, whereinR¹, R², R³ and R⁴ are all methyl, or together with the carbon atoms towhich they are attached form a phenyl ring; andR⁵ is —(C1-C6)alkyl or benzyl.

In another preferred embodiment there is provided the above describedprocess wherein R¹ to R⁴ are all methyl; and R⁵ is ethyl.

In still another embodiment according to the present invention there isprovided the above described process a) to d) for the manufacture of thecompound of formula 1, wherein

steps a) and b) are as described above; and

c-1) said compound of formula 5 according to step b) is further reactedin the presence of a palladium catalyst and a base, which can both bethe same or different as under step a), and the compound of formula D

followed by treatment with an acid to give the compound of formula 8

and

d) said compound of formula 8 is further reacted with the compound offormula 9

In the presence of (C001)₂ and AlCl₃, to give the compound of formula 1,and R¹ to R⁵ are as defined above.

In still another preferred embodiment according to the present inventionthere is provided the process for the manufacture of the compound offormula 1 according to steps a) to d) above, wherein

a) the compound of formula 2

is reacted in the presence of PdCl₂(dppf)CH₂Cl₂, Pd(OAc)₂, Na₂CO₃ andthe compound of formula 3

to give the compound of formula 4

b) said compound of formula 4 is further reacted in the presence ofN-iodosuccinimide (NIS) and CF₃COOH, or N-bromosuccinimide (NBS) to givea compound of formula 5

wherein X is —I (5a) or —Br (5b);

c-1) said compound of formula 5 is further reacted in the presence ofPdCl₂(dppf)CH₂Cl₂, LiOH and the compound of formula 6,

and subsequently treated with HCl to give the compound of formula 8

and

d) said compound of formula 8 is further reacted with the compound offormula 9

In the presence of (C001)₂ and AlCl₃, to give the compound of formula 1.

In an especially preferred embodiment according to the presentinvention, the reaction step b) prior to the reaction step c-1) asmentioned above is carried out in the presence of NBS to give thecompound of formula 5, wherein X is bromo (5b).

In yet another embodiment according to the present invention there isprovided a process for the manufacture of the compound of formula 1,wherein reaction steps a) and b) are as described herein before; and

c-2) the compound of formula 5 from reaction step b) is further reactedin the presence of a palladium catalyst and a base, which may both bethe same or different as in step a), CuI, tetramethylguanidine (TMG) andthe compound of formula 7,

followed by the reaction with a strong base, to give the compound offormula 8

and

d) said compound of formula 8 is further reacted with the compound offormula 9

In the presence of (C001)₂ and AlCl₃, to give the compound of formula 1.

In a still preferred embodiment according to the present invention,there is provided the process for the manufacture of the compound offormula 1 according to steps a) to d) above, wherein

a) the compound of formula 2

is reacted in the presence of PdCl₂(dppf)CH₂Cl₂, Pd(OAc)₂, Na₂CO₃ andthe compound of formula 3

to give the compound of formula 4

b) said compound of formula 4 is further reacted in the presence ofN-iodosuccinimide (NIS) and CF₃COOH, or N-bromosuccinimide (NBS) to givea compound of formula 5

wherein X is —I (5a) or —Br (5b);c-2) said compound of formula 5 is further reacted in the presence ofPd(PPh₃)₂Cl₂, CuI, tetramethylguanidine (TMG) and the compound offormula 7,

followed by the reaction with KOtBu in NMP, to give the compound offormula 8

and

d) said compound of formula 8 is further reacted with the compound offormula 9

In the presence of (COCl)₂ and AlCl₃, to give the compound of formula 1.

In still another preferred embodiment there is provided the process asdescribed above, wherein the reaction step b) prior to the reaction stepc-2) is carried out in the presence of NBS to give the compound offormula 5, wherein X is bromo (5b).

General Synthesis Route

The reaction partners and conditions of the above-mentionedSuzuki-Miyaura-, Sonogashira- and Friedel Crafts reactions are generallyknown to the person of skill in the art of synthetic organic chemistryand are inter alia described or referred to in common textbooks ofOrganic Chemistry. If not explicitly otherwise stated, the abovedescribed preferred reaction conditions to obtain the compound offormula 1 can be summarized, but not limited, according to the followinggeneral reaction scheme 1. The key reaction step according to thepresent invention, namely the reactions from compound 5 to 8, can beaccomplished either via the reaction with a compound D, preferably thecompound 6 (Suzuki-Miyaura Route) or via the reaction with compound 7(Sonogashira Route):

In accordance with the present invention, the reaction partner of thefirst Suzuki-Miyaura reaction is 4-chlorophenylboronic acid (3). Thereaction partner of the second Suzuki-Miyaura reaction is a vinyl etherboronate of formula (D), such as catechol vinylboronate or pinacolvinylboronate (1-ethoxyethene-2-boronic acid pinacol ester, 6), with thepinacol vinylboronate being especially preferred. If not explicitlyotherwise stated the compounds (D) or (6) are present as mixtures oftheir E/Z isomers.

The reaction is carried out in the presence of palladium (Pd) catalysts,more preferably, PdCl₂(dppf)CH₂Cl₂, Pd(OAc)₂ and the like. In addition,both Suzuki-Miyaura reactions take place under basic conditions(pH-values above 7) in organic solvents or mixtures of organic solventswith water. Preferred bases according to the present invention areorganic bases or alkali metal bases, more particularly N(CH₂CH₃)₃,Na₂CO₃, LiOH and the like. Preferred organic solvents are toluene,dimethylformamide (DMF) or mixtures of dioxane and water.

Subsequent to the second Suzuki-Miyaura reaction the compound of formula(8) is obtained by cyclization-reaction in the presence of an acid.Suitable acids are well known to the person of skill in the art andencompass organic and inorganic or mineral acids. Preferred acidsaccording to the present invention are HCl, H₂SO₄, HNO₃, CF₃COOH and thelike; with HCl being especially preferred.

According to the present invention, the preferred reaction partner inthe Sonogashira reaction is ethynyltrimethylsilane (7). The reaction ispreferably carried out in the presence of Pd(PPh₃)₂Cl₂ and CuI intoluene. Strong bases in N-methyl-2-pyrrolidone (NMP) subsequently usedin the reaction to obtain the compound of formula (8) are bases with ahigher strength than those used in the Suzuki-Miyaura reactions togetherwith the palladium catalysts as described before. Such strong bases arepreferably alkali metal alcoholates and the like. Especially preferredaccording to the present invention is KOtBu used inN-methyl-2-pyrrolidone (NMP).

The Suzuki-Miyaura- and Sonogashira reactions are preferably carried outin a temperature range between 70 and 120° C., or under reflux of thesolvent or solvent mixture used.

The final Friedel-Crafts reaction, also named Friedel-Crafts acylation,preferably takes place in the presence of (COCl)₂ and AlCl₃ in DMF andCH₂Cl₂ at room temperature (rt).

The term “room temperature” (rt) as used herein means the ambienttemperature of the place where the reaction is carried out without anyadditional heating or cooling. According to the present invention, roomtemperature is preferably between 18 and 26° C., more preferably 20 to24° C.

The term —(C1-C6)alkyl as used herein means a linear or branched,saturated hydrocarbon containing from one to six carbon-atoms,preferably from 2 to 4 carbon-atoms. The most preferred —(C1-C6)alkylgroup according to the present invention is ethyl.

The term “halogenation reaction” as mentioned above is a reaction of theproduct of the first Suzuki-Miyaura reaction with a “halogenatingreagent” selected from either N-iodosuccinimide (NIS) to introduce oneiodo-atom or others (e.g. I₂); or N-bromosuccinimide (NBS) to introduceone bromo-atom in said product of the first Suzuki-Miyaura reaction. Thereaction with NIS is preferably carried out in the presence oftrifluoroacetic acid (TFA) and DMF. The reaction with NBS is preferablycarried out in DMF.

INTERMEDIATES I) 5-substituted-7-azaindoles

One of the key features in the synthesis route towards the formula 1according to the present invention is the new and improved method toobtain the compound of formula 8. Due to these improvements, the abovedescribed synthesis routes provide for the first time a process for themanufacture of the compound of formula 1 which is faster, cheaper andsafer than the previously described processes.

Based on this, a further embodiment of the present invention is toprovide a process for the manufacture of a compound of formula A,

said process being characterized in thata) a compound of formula B

is reacted in the presence of a halogenation reagent, optionallyfollowed by the introduction of amino-protecting groups, to give acompound of formula C

b) said compound of formula C is further reacted in the presence of apalladium catalyst, a base and a compound of the formula D or 7

to give the compound of formula E or F, respectively

and

c-1) the compound of formula E is further treated with an acid; or

c-2) the compound of formula F is further treated with a strong base; togive a compound of formula A; wherein

-   R is phenyl, which is unsubstituted or once or several times    substituted by halogen, or —Br;-   R¹, R², R³ and R⁴ are all methyl, or together with the carbon atoms    to which they are attached form a phenyl ring;-   R⁵ is —(C1-C6)alkyl or benzyl;-   X is —Br or —I; and-   Y¹ and Y² are each independently selected from the group consisting    of benzyl, trifluoroacetyl, acetyl, and hydrogen.

The compounds of formula E and F as defined above are novel and formanother embodiment of the present invention.

If not explicitly otherwise stated, the compounds of formula (D) and (E)are present as mixtures of their E/Z isomers.

The term “halogenation reagent” as used herein means N-bromosuccinimide(NBS), N-iodosuccinimide (NIS) or sodiumperiodate in combination withiodine (I₂/NaIO₄). For the iodination of a compound of formula B, theuse of NIS in the presence of trifluoroacetic acid (TFA) is especiallypreferred.

The term —(C1-C6)alkyl as used herein means a linear or branched,saturated hydrocarbon containing from one to six carbon-atoms,preferably from 2 to 4 carbon-atoms. The most preferred —(C1-C6)alkylgroup according to the present invention is ethyl.

The term “amino-protecting groups” as used herein means any protectinggroup known to the person of skill in the art of organic chemistry toprotect an amino group against reactions. Preferred amino protectinggroups according to the present invention are benzyl, trifluoroacetyland acetyl.

Preferred palladium catalysts and bases as used in the process to obtainthe compounds of formula A are the same as described above in connectionwith the reactions according to scheme 1. In particular, the reactionstep b) which leads to a compound of formula E as described above ispreferably carried out in the presence of PdCl₂(dppf)CH₂Cl₂ as Palladiumcatalyst, and LiOH as base. The reaction step b) which leads to acompound of formula F as described above is preferably carried out inthe presence of Pd(PPh₃)₂Cl₂, CuI and tetramethylguanidine (TMG).

The term “strong bases” means bases with a higher strength than thoseused in the Suzuki-Miyaura reactions together with the palladiumcatalysts as described above. Preferably the term “strong bases” meansalkali metal alcoholates and the like. An especially preferred strongbase according to the present invention is KOtBu, which is preferablyused in N-methyl-2-pyrrolidone (NMP).

The term “acid” as used herein means organic- and inorganic or mineralacids. Preferred acids according to the present invention are HCl,H₂SO₄, HNO₃, CF₃COOH and the like; with HCl being especially preferred.

In a preferred embodiment of the present invention there is provided aprocess for the manufacture of a compound of formula A as describedabove,

said process being characterized in thata) a compound of formula B

is reacted in the presence of N-bromosuccinimide (NBS) orN-iodosuccinimide (NIS) or sodiumperiodate in combination with iodine(I₂/NaIO₄), optionally followed by the introduction of amino-protectinggroups, to give a compound of formula C

b) said compound of formula C is further reacted in the presence ofPdCl₂(dppf)CH₂Cl₂, LiOH and a compound of the formula D

to give the compound of formula E

and

c-1) the compound of formula E is further treated with HCl,

to give a compound of formula A; wherein

-   R is phenyl, which is unsubstituted or once or several times    substituted by halogen, or —Br;-   R¹, R², R³ and R⁴ are all methyl, or together with the carbon atoms    to which they are attached form a phenyl ring;-   R⁵ is —(C1-C6)alkyl or benzyl;-   X is —Br or —I; and-   Y¹ and Y² are each independently selected from the group consisting    of benzyl, trifluoroacetyl, acetyl, and hydrogen.

In a preferred embodiment according to the present invention there isprovided the process to obtain the compound of formula A, via thecompound of formula E and reaction step c-1), as described above,wherein

R is —Br, and all remaining substituents are as defined above.

In another preferred embodiment according to the present invention thereis provided the process to obtain the compound of formula A, via thecompound of formula E and reaction step c-1), as described above,wherein

R is —Br;

R¹ to R⁴ are all methyl;R⁵ is ethyl;

X is —I; and

Y¹ and Y² are both hydrogen.

In another preferred embodiment according to the present invention thereis provided the process to obtain the compound of formula A, via thecompound of formula E and reaction step c-1), as described above,wherein

R is 4-Cl-phenyl, and all remaining substituents are as defined above.

In another preferred embodiment according to the present invention thereis provided the process to obtain the compound of formula A, via thecompound of formula E and reaction step c-1), as described above,wherein

R is 4-Cl-phenyl;

R¹ to R⁴ are all methyl;R⁵ is ethyl;

X is —Br; and

Y¹ and Y² are both hydrogen.

In a further embodiment of the present invention there is provided theprocess for the manufacture of a compound of formula A, via the compoundof formula F and reaction step c-2) as described above,

said process being characterized in thata) a compound of formula B

is reacted in the presence of N-bromosuccinimide (NBS) orN-iodosuccinimide (NIS) or sodiumperiodate in combination with iodine(I₂/NaIO₄), optionally followed by the introduction of amino-protectinggroups, to give a compound of formula C

b) said compound of formula C is further reacted in the presence ofPd(PPh₃)₂Cl₂, CuI, tetramethylguanidine and the compound of the formula7

to give a compound of formula F

and

c-2) said compound of formula F is further reacted in the presence ofKOtBu to give a compound of formula A; wherein

-   R is phenyl, which is unsubstituted or once or several times    substituted by halogen, or —Br;-   X is —Br or —I; and-   Y¹ and Y² are independently selected from the group consisting of    benzyl, trifluoroacetyl, acetyl, and hydrogen.

In a preferred embodiment according to the present invention, there isprovided the process for the manufacture of the compounds of formula (A)via the compounds of formula (F) as described above, wherein

the reaction step a) is carried out in the presence of N-iodosuccinimide(NIS) and trifluoracetic acid;the reaction step b) is carried out in the presence of Pd(PPh₃)₂Cl₂,CuI, tetramethylguanidine and the compound of formula 7 in toluene;the reaction step c-2) is carried out in the presence of KOtBu inN-methyl-2-pyrrolidon; and

R is —Br;

X is —I; and

Y¹ and Y² are both hydrogen.

II) Pinacol Vinylboronates

According to the present invention, the above described improvedsynthesis of the compounds of formula A, and subsequently also of thecompound of formula 1, is in particular based on the use ofvinylboronates in the corresponding Suzuki-Miyaura reactions which leadto the compounds of formula A, in particular the 5-Br-7-azaindole andthe 5-(4-Cl-phenyl)-7-azaindole. The use of vinylboronates and theirpreparation is generally known in the art.

Catechol vinylether boronate (the compound of formula D, wherein R¹ toR⁴ together with the carbon-atoms to which they are attached form aphenyl ring) can be prepared according to the procedure described inSatoh, M.; Miyaura, N.; Suzuki, A.; Synthesis 1987, 373 and according tothe following reaction scheme 2:

Pinacol vinylether boronate (the compound of formula D, wherein R¹ to R⁴are all methyl) can be prepared according to the reaction scheme 3below.

However, both synthesis routes use highly flammable ethoxyacetylene,which leads to tremendous safety concerns when used on an industrialscale.

Vinylether boronates have also been prepared using dehydrogenativeborylation of alkenes. This reaction consists of a catalytichydroboration of an alkene with a monohydrido borane, followed by theelimination of hydrogen. Rhodium, titanium and ruthenium catalysts areoften used in this type of reaction. A main issue with these catalystsis that many are also efficient hydrogenation catalysts and thereforecompeting hydrogenation and hydroboration can occur under the reactionconditions.

There remains a need to find catalysts able to perform thedehydrogenative borylation without competing hydroboration orhydrogenation of the vinylboronate and to overcome the above describedsafety issues.

It has now surprisingly been found that with certain rhodium-,ruthenium- or palladium catalysts out of a list of commonly usedcatalysts the desired pinacol vinylether boronate was formed almostexclusively. Only small amounts (ca. 3%) of the hydroboration productcould be detected.

Consequently, in another embodiment of the present invention, there isprovided a process for the manufacture of the compounds of formula D

wherein the compound of formula G

is reacted with a compound of formula H

in the presence of a palladium, rhodium or ruthenium-catalyst to give acompound of formula D, whereinR¹, R², R³ and R⁴ are all methyl, or together with the carbon atoms towhich they are attached form a phenyl ring; andR⁵ is —(C1-C6)alkyl or benzyl.

In a preferred embodiment there is provided the above described processfor the manufacture of the compounds of formula D, wherein

R¹, R², R³ and R⁴ are all methyl; andR⁵ is ethyl.

In another preferred embodiment the above described process for themanufacture of the compounds of formula D is carried out in the presenceof Pd(OAc)₂, Pd₂ (dba)₃, Pd(NO₃)₂, Pd/C (5%), PdCl₂, Rh(OAc)₂ or RuCl₃.

In another preferred embodiment the above described process for themanufacture of the compounds of formula D is carried out in the presenceof 0.05 to 0.5 mol % Pd(OAc)₂ at room temperature.

The term “room temperature” (rt) as used herein means the ambienttemperature of the place where the reaction is carried out without anyadditional heating or cooling. According to the present invention, roomtemperature is preferably between 18 and 26° C., more preferably 20 to24° C.

The invention is now illustrated by the following accompanying, notlimiting examples.

EXAMPLES Example 1 2-amino-5-(4-chlorophenyl)-pyridine (4, firstSuzuki-Miyaura reaction)

2-Amino-5-bromopyridine (2) was reacted with 4-chlorophenylboronic acid(3) in dioxane/water in the presence of 2.2 equivalents of Na₂CO₃ and 1mol % Pd(OAc)₂ plus 1 mol % PdCl₂(dppf).CH₂Cl₂ at 90° C. for 1.5 h.After cooling to room temperature the product (4) was precipitated asthe HCl salt by adding HCl (25%, 6 equiv) followed by removal of dioxaneunder vacuum. The salt was filtered, digested in diethylether, filteredand then converted to the free amine by treatment with aqueous NaOH.After filtration, the product was isolated in 78% yield. Alternatively,the product has been isolated by chromatography in 83% yield. MS (TurboSpray): 207 (52%), 205 (M+H⁺, 100%), 170 (9%).

Example 2 Halogenation of 2-amino-5-(4-chlorophenyl)-pyridine (4)

2-Amino-5-(4-chlorophenyl)-pyridine (4) was converted to theaminopyridine iodide (5a) and the aminopyridine bromide (5b). Iodinationof (4) using iodine and AgSO₄ gave only 75% conversion after 3 days atroom temperature. Better results were obtained with NIS/TFA. Thepyridine bromide could be prepared using NBS.

a) Iodination of (4)

To a solution of (4) and trifluoroacetic acid (1.2 equiv) in DMF wasadded N-iodosuccinimide (NIS, 1.1 equiv) in DMF. After stirring for 2.5h at 80° C., the reaction was complete. After aqueous workup, theproduct 5a was isolated in 98% yield. MS (Turbo Spray): 331 (100%), 205(42%), 122 (19%).

b) Bromination of (4)

To a solution of (4) in DMF was added N-bromosuccinimide and theresulting reaction solution was stirred at room temperature for 1 h.After adding the solution to water, the product precipitated and thenwas filtered. Minor impurities were removed by digesting the product inhexanes. The aminopyridine bromide (5b) was isolated in a yield of 91%.MS (GC-Split): 284 (100%), 282 (77%, M), 168 (34%), 151 (14%), 140(18%), 113 (10%).

Example 3 5-(4-Cl-phenyl) azaindole (8, via second Suzuki-Miyaurareaction) I. Pinacol Vinylboronate Coupling

I-a) Cyclization of the Iodide (5a):

To a mixture of iodide (5a) and pinacol vinylboronate (6, 1.3 equiv) inDMF was added LiOH (3 equiv) followed by PdCl₂(dppf).CH₂Cl₂ (3 mol %)under an inert atmosphere (Ar). The reaction mixture was heated to 70°C. and stirred for 18 h. HPLC analysis indicated complete conversion tothe vinylether “Intermediate-A” (MS: (Turbo Spray) 277 (33%), 275 (M+H⁺,100%), 231 (22%), 229 (84%), 205 (11%)). After cooling to 50° C., 25%HCl (15 equiv) was added. The mixture was kept at this temperature for 1h. After workup, the azaindole 8 was isolated as a crystalline solid in92% yield. MS (Turbo Spray): 231 (26%), 229 (M+H⁺, 100%).

I-b) Cyclization of the Bromide:

To a mixture of bromide (5b) and pinacol vinylboronate (6, 1.2 equiv) inDMF was added LiOH (3 equiv) followed by PdCl₂(dppf).CH₂Cl₂ (3 mol %).The reaction mixture was heated to 70° C. and stirred for 18 h. HPLCanalysis indicated complete conversion to the vinylether intermediate.After cooling the reaction mixture to 50° C., HCl (25%) was added andthe mixture was stirred at this temperature for 1 h. The reaction wascomplete at this point. After workup, compound 8 was isolated as acrystalline solid in 78% yield. MS (Turbo Spray): 231 (35%), 229 (M+H⁺,100%).

II. Catechol Vinylboronate Coupling

To a mixture of iodide (5a) and catechol vinylboronate (6a, 1.1 equiv)in dioxane/water (80:20) was added LiOH (3 equiv) followed byPdCl₂(dppf).CH₂Cl₂ (3 mol %). The reaction mixture was heated to 80° C.and stirred for 24 h. HPLC analysis indicated complete conversion to thevinylether intermediate. After cooling to 50° C., 25% HCl (15 equiv) wasadded and the mixture was kept at this temperature for 1 h. Afterworkup, the azaindole 8 was isolated as a crystalline solid in 68%yield. MS (Turbo Spray): 231 (26%), 229 (M+H⁺, 100%)

Example 4 Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(1)

A suspension of sulfonamide acid (9) (1.2 eq.) in CH₂Cl₂ was treated atroom temperature with cat. amount of DMF (0.11 eq.). Within 30 min asolution of oxalylchloride (1.30 eq.) in CH₂Cl₂ was added and thereaction mixture was stirred for 2 h, whereby the corresponding acidchloride was formed. A suspension of aluminium chloride (AlCl₃, 4 eq.)in CH₂Cl₂ was treated at 0° C. with a solution of CI-phenyl azaindole(8) in CH₂Cl₂. To the reaction mixture was subsequently added at roomtemperature the freshly prepared (above described) acid chloride.Stirring at room temperature for 3 h, aqueous work-up andcrystallization from THF/heptane provided the title compound (1) asoff-white powder in 85% yield. MS (Turbo Spry): 509 (48%), 507 (M+NH₄ ⁺,100%), 492 (40%), 490 (M+H⁺, 84%).

Example 5 5-(4-Cl-phenyl)azaindole (8, via Sonogashira reaction)

A solution of bromide 5b in toluene was degassed with argon and thentreated with PdCl₂(PPh₃)₂Cl₂ (0.17 eq.) and CuI (0.17 eq.) and degassedwith argon again. To the suspension was added tetramethylguanidine (1.4eq.) and ethyltrimethylsilane (2 eq.) and stirred at 100° C. for 2 h.After cooling to room temperature, extractive work-up andchromatographic purification the intermediate F was collected in 93%yield. MS (Turbo Spray): 303 (49%), 301 (M+H⁺, 100%)

A solution of the intermediate F in 1-methyl-2-pyrrolidinone (NMP) wastreated at room temperature with potassium tert. butylate (2 eq.). Themixture was heated to 120° C. and stirred for 2 h. After cooling to roomtemperature, extractive work-up and crystallization from EtOH/water thetitle compound (8) was collected in 80% yield. MS (Turbo Spray): 231(26%), 229 (M+H⁺, 100%)

Intermediate X: MS (Turbo Spray): 231 (41%), 229 (M+H⁺, 100%) Example 62-amino-5-bromo-3-iodopyridine (11)

a) NIS Procedure:

To a solution of 2-amino-5-bromopyridine (2) in DMF was addedtrifluoroacetic acid (1.2 equiv). At room temperature, N-iodosuccinimide(1.1 equiv) was added and the reaction mixture was heated at 50° C. for3 h. HPLC indicated complete conversion. After cooling to roomtemperature the product was precipitated by adding the reaction mixtureto water. After neutralization with sodiumthiosulfate and 1N NaOH thetitle compound (11) was collected by filtration as a brown solid in 90%yield.

b) I₂/NaIO₄ procedure:

To a solution of 2-amino-5-bromopyridine (2) in acetonitrile was addedsodiumperiodate (0.4 equiv) and iodine (0.65 equiv). Trifluoroaceticacid (0.65 equiv) was added over 15 min and the reaction mixture washeated at 80° C. overnight. HPLC indicated 96% conversion at this point.An aqueous solution of sodium sulfite was added, followed by more waterto precipitate the product which was filtered off and washed with water.The title compound (11) was isolated as a brown crystalline solid in 75%yield. MS (Turbo Spray): 298 (M+H⁺, 100%)

Example 7 5-bromo-7-azaindole (12, via Suzuki-Miyaura reaction)

2-Amino-3-iodo-5-bromopyridine (11) was reacted with pinacolvinylethylether boronate (6, 1.3 equiv) in the presence of LiOH (3equiv) and PdCl₂(dppf).CH₂Cl₂ (1 mol %). After 18 h at 70° C., completeconversion to the amino pyridine vinyl ether was observed(Intermediate-C). The vinyl ether was immediately hydrolyzed by adding25% HCl and stirring the reaction mixture at 50° C. for 1 h. Workup andcrystallization from toluene/heptane gave the title compound (12) in 87%yield. MS (Turbo Spray): 199 (M+H⁺, 100%). Intermediate: MS (TurboSpray): 243 (M+H⁺), 199.

Example 8 5-bromo-7-azaindole (12, via Sonogashira reaction)

A solution of 2-Amino-3-iodo-5-bromopyridine (11) in toluene wasdegassed with argon and then treated with PdCl₂(PPh₃)₂Cl₂ (0.17 eq.) andCuI (0.17 eq.) and degassed with argon again. To the suspension wasadded tetramethylguanidine (1.4 eq.) and ethyltrimethylsilane (2 eq.)and stirred at 80° C. for 1 h. After cooling to room temperature,extractive work-up the intermediate was collected in 83% yield as brownsolid.

A solution of the intermediate in 1-methyl-2-pyrrolidinone (NMP) wastreated at room temperature with potassium tert. butylate (2 eq.). Themixture was heated to 80° C. and stirred for 1 h. After cooling to roomtemperature, extractive work-up and chromatographic purification thetitle compound (12) was collected in non optimized 53% yield.

Example 9 Pinacol Vinylboronate (6)

Pinacolborane (10) and 4.1 equivalents of ethyl vinylether are stirredat room temperature in the presence of 0.05 mol % Pd(OAc)₂ untilreaction completion (20 h). The mixture is then concentrated and theproduct distilled under vacuum to afford pinacol vinylboronate (6) as acolorless liquid in 83% yield. The product consists of a mixture of E/Zisomers (ratio ca. 2:1). MS (Turbo Spray): 199 (M+H⁺, 100%), 216 (M+NH₄⁺).

1. A process for the manufacture of a compound of formula 1,

comprising at least one Suzuki-Miyaura reaction followed by aFriedel-Crafts acylation.
 2. The process for the manufacture of thecompound of formula 1 according to claim 1, wherein a) a compound offormula 2

is reacted in the presence of a palladium catalyst, a base, and acompound of formula 3

in a Suzuki-Miyaura reaction to give a compound of formula 4

b) the compound of formula 4 is further reacted in the presence of ahalogenation reagent to give a compound of formula 5 wherein X is I (5a)or Br (5b); and

the compound of formula 5 is further reacted in the presence of eitherc-1) a compound of formula (D); or c-2) a compound of formula 7 in aSonogashira reaction

to give a compound of formula 8

and d) the compound of formula 8 is subsequently reacted in the presenceof a compound of formula 9 and under conditions of a Friedel-CraftsAcylation

to give the compound of formula 1, wherein R¹, R², R³, and R⁴ are allmethyl, or together with the carbon atoms to which they are attachedform a phenyl ring; and R⁵ is —(C1-C6)alkyl or benzyl.
 3. The processaccording to claim 2, wherein the palladium catalyst and base inreaction step (a) are PdCl₂(dppf)CH₂Cl₂, Pd(OAc)₂, and Na₂CO₃; thehalogenation reagent in reaction step (b) is N-iodosuccinimide (NIS) andCF₃COOH, or is N-bromosuccinimide (NBS); the compound of formula 5 isreacted in reaction step (c-1) in the presence of PdCl₂(dppf)CH₂Cl₂,LiOH, and the compound of formula (D), where the compound of formula (D)is the compound of formula 6

and the Friedel-Crafts Acylation in reaction step (d) occurs in thepresence of (COCl)₂ and AlCl₃.
 4. The process according to claim 3,wherein the reaction step (b) is carried out in the presence ofN-bromosuccinimide to give the compound of formula 5b, wherein X isbromo.
 5. The process according to claim 2, wherein wherein thepalladium catalyst and base in reaction step (a) are PdCl₂(dppf)CH₂Cl₂,Pd(OAc)₂, and Na₂CO₃; the halogenation reagent in reaction step (b) isN-iodosuccinimide (NIS) and CF₃COOH, or is N-bromosuccinimide (NBS); thecompound of formula 5 is reacted in reaction step (c-2) in the presenceof PdCl₂(dppf)CH₂Cl₂, CuI, TMG, and the compound of formula (7),followed by reaction with KOtBu, to give the compound of formula 8; andthe Friedel-Crafts Acylation in reaction step (d) occurs in the presenceof (COCl)₂ and AlCl₃. 6-15. (canceled)
 16. The process of claim 2,wherein R¹, R², R³, and R⁴ are all methyl.
 17. The process of claim 2,wherein R⁵ is —(C1-C6)alkyl.
 18. The process of claim 17, wherein R⁵ isethyl.
 19. The process of claim 2, wherein X is Br.
 20. The process ofclaim 2, wherein the compound of formula 5 is further reacted in thepresence of the compound of formula (D).
 21. The process of claim 2,wherein the compound of formula 5 is further reacted in the presence ofthe compound of formula 7 in a Sonogashira reaction.